CHEMORESISTANCE OF MALIGNANT-MELANOMA - M ECHANISMS AND POSSIBLE MODULATION

Response rates of metastatic malignant melanoma to cytostatic treatmen t are disappointingly low. Although immunomodulators such as interfero ns are more commonly being used in combination with cytostatics, no ma jor breakthrough has been achieved. The mechanisms underlying the high chemoresistance of melanoma cells are so far ill-defined, and investi gations are only just being initiated. Several mechanisms of chemoresi stance have, however, been studied with other tumours and might be rel evant for human melanoma: (1) ''Classical'' multidrug resistance, dete rmined by the expression of the p-glycoprotein which resembles a membr ane pump that eliminates natural and synthetic agents from the cell in terior. Different drugs, including calcium antagonists, interfere with its function and can thus modulate chemoresistance. Preliminary data from investigations of these mechanisms indicate that p-glycoprotein i s not, however, involved in the multidrug resistance of malignant mela noma. (2) Detoxification, involving glutathione-S-transferases (GST). GST are a multigene family of enzymes which inactivate alkylating agen ts by conjugation to glutathione. Their relevance for chemoresistance in melanoma has not yet been clarified. (3) Topoisomerase II, which is involved in DNA recombination and DNA transcription events and repres ents the target of several inhibitory cytotoxic agents. Low levels of the enzyme render cells resistant to the action of specific drugs. Aga in nothing is yet known regarding the relevance of this mechanism in h uman melanoma. Further studies of these potentially important resistan ce mechanisms are thus urgently needed in order to develop more effect ive therapies for advanced malignant melanoma.